Frontotemporal lobar degeneration (FTLD) is a group of dementing illnesses with devastating consequences that preferentially affect individuals in late middle age. Neocortical involvement in the frontal and temporal lobes leads to major alterations in behavior and affects cognition, including language function. Unfortunately, there are currently no substantial therapies for the treatment of these diseases. The recent identification that mutations in tau can cause FTLD and that it is the hyperphosphorylation of the mutant tau that leads to aggregation, has established an entirely novel drug target for treatment of FTLD and similar disorders such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), It has long been known that small molecule inhibitors of Hsp90 can lead to the enhanced degradation of mutated and misfolded proteins. In fact, natural product and synthetic Hsp90 inhibitors are in various stages of clinical development as anti- cancer agents. One such drug, SNX-5422, is a potent inhibitor of Hsp90 and is particularly attractive in that it can achieve, following oral dosing, substantial and sustained plasma levels. It appears to be well tolerated to date and is currently being evaluated in multiple phase I trials. More recently, it has been discovered that Hsp90 inhibitors can cause the preferential degradation of abnormally phosphorylated tau both in vitro and in vivo. Unfortunately, SNX-5422 does not appear to cross the blood brain barrier at appreciable levels making this and closely related compounds not likely to be useful for treating CNS disorders such as FTLD. Clearly, novel analogues are necessary for the treatment of CNS disorders. Fundamentally, therefore, we propose in this application to exploit the known chemical space with respect to inhibitors of Hsp90 to identify compounds that maintain inhibition while simultaneously having physicochemical properties compatible with crossing the blood brain barrier (BBB). The initial positive results provide a proof of concept and suggest that a dedicated and funded drug discovery effort offers the real possibility of identifying Hsp90 inhibitors suitable for clinical development targeting FTLD. The ultimate goal of this overall proposal is to provide enough data to determine a go / no go decision for the filing of an Investigational New Drug application (IND) with the FDA. Public Health Relevance: We propose to develop and characterize small compounds called Hsp90 inhibitors as potential therapeutics for the treatment of tauopathies including frontotemporal degeneration. If these studies are successful, we can move into Clinical Phase I trials. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.